Genetic alteration profile and T Cell receptor repertoire in severe immune-related adverse events during checkpoint immunotherapy

BackgroundImmune-related adverse events (irAEs) are negative effects during immunotherapy that could lead to malignant therapeutic events and even death, particular in grade 3-5 (SirAEs). Inherited alterations and diversity of the T cell receptor (TCR) repertoire could potentially discriminate SirAEs. Here we present the study of interpreting genetic alterations and TCR repertoire between post-ICIs-treatment SirAEs and non-SirAEs populations.MethodsPatients received immune checkpoint inhibitors (ICIs) treatment from Nov 2021 to Dec 2023 were recruited with follow-up. Peripheral blood were collected at baseline, SirAEs occurred during or after immnuno-therapy within 3 months (4 cycles). Genetic DNA of was extracted then underwent whole exome sequencing and TCR repertoire sequencing. Germline mutations were compared between SirAEs and non-SirAEs populations, with TCR analysis including diversity index and cluster analysis.ResultsAmong 328 patients, 31( 9.45%) patients ocurred SirAEs. 96 in 328 patients were selected into the analysis. Germline WES found that alternations of 329 sites/227 genes showed significant difference between SirAEs and non-SirAEs group (116 vs 43, p<0.05), in which 75 unique genes in SirAEs containing nonsynonymous substitution, and function enriched in regulation of innnate and immune response and cell recognition. Results of TCR showed convergence score significant difference between SirAEs and non-SirAEs at baseline, while no difference in other diversity index. TRBV10, 24, 28, are more preferred in SirAEs group CDR3aa, as well as lysine and valine. 17 paired SirAEs samples were identified lower clonetypes at both baseline and SirAEs timepoint compare to 19 non-SirAEs, while the non-SirAEs experienced relative drastic change than the SirAEs at the same time point.ConclusionsStudy results indicate that the specific hereditary genetic profile and TCR repertoire features may consider as indicator of SirAEs in immunotherapy, which highlights the complex interplay and further investigation of SirAEs and personalized patient care in immunotherapy.Clinical trial identificationChiCTR2100052367.Legal entity responsible for the studyThe authors.FundingHas not received any funding.DisclosureY. Lin, S. Chen: Financial Interests, Personal, Full or part-time Employment: Haplox Biotechnology Co.,Ltd. All other authors have declared no conflicts of interest.